Effects of Whole Body Irradiation on Morphine, DAMGO, DPDPE, U50,488H and beta-endorphin-Induced Antinociception

Opioid receptors have been pharmacologically classified as micro, delta, kappa and epsilon. We have recently reported that the antinociceptive effect of morphine (a micro-opioid receptor agonist), but not that of beta-endorphin (a novel micro/epsilon-opioid receptor agonist), is attenuated by whole body irradiation (WBI). It is unclear at present whether WBI has differential effects on the antinociceptive effects of micro-, delta-, kappa- and epsilon-opioid receptor agonists. In our current experiments, male ICR mice were exposed to WBI (5Gy) from a 60Co gamma-source and the antinociceptive effects of opioid receptor agonists were assessed two hours later using the hot water (52degrees C) tail-immersion test. Morphine and D-Ala2,N-Me-Phe4,Gly-olenkephalin(DAMGO), [D-Pen2-D-Pen5]enkephalin (DPDPE), trans-3,4-Dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide (U50,488H), and beta-endorphin were tested as agonists for micro, delta, kappa, and epsilon-opioid receptors, respectively. WBI significantly attenuated the antinociceptive effects of morphine and DAMGO, but increased those of beta-endorphin. The antinociceptive effects of DPDPE and U50,488H were not affected by WBI. In addition, to more preciously understand the differential effects of WBI on micro- and epsilon-opioid receptor agonists, we assessed pretreatment effects of beta-funaltrexamine (beta-FNA, a micro-opioid receptor antagonist) or beta-endorphin1-27 (beta-EP1-27, an epsilon-opioid receptor antagonist), and found that pretreatment with beta-FNA significantly attenuated the antinociceptive effects of morphine and beta-endorphin by WBI. beta-EP1-27 significantly reversed the attenuation of morphine by WBI and significantly attenuated the increased effects of beta-endorphin by WBI. The results demonstrate differential sensitivities of opioid receptors to WBI, especially for micro- and epsilon-opioid receptors.

Doença de Wilson em crianças e adolescentes: como fazer diagnóstico precoce / Wilson's disease in children and adolescent: a key to an early diagnosis

A doença de Wilson é uma desordem autossômica recessiva do metabolismo do cobre, que leva à impregnação desse metal em diversos tecidos como o fígado, cérebro, córnea e rins. Tem prevalência de 1:40.000 e evolui de forma progressiva e fatal se não tratada. Seu diagnóstico depende de suspeição clínica e exames laboratoriais, podendo ser difícil nos pacientes assintomáticos ou com insuficiência hepática grave. A tríade clássica de apresentação é hepática, neurológica e oftalmológica. Na criança, a forma de apresentação mais comum é a hepática (aguda ou crônica). Os critérios diagnósticos são baseados na presença de ceruloplasmina baixa, cobre em urina de 24 horas e cobre livre elevados e avaliação oftalmológica à procura do anel de Kayser-Fleischer. O tratamento medicamentoso deve ser instituído o quanto antes, de forma a evitaremse as lesões teciduais do excesso de cobre, daí a grande importância do diagnóstico precoce. A droga de escolha é a D-penicilamina, mas é necessário o monitoramento de seus possíveis efeitos colaterais e eventuais pioras do quadro neuropsiquiátrico. Existem outras drogas, como a trientina, tetratiomolibdato e o zinco, que também têm efeito na redução do cobre orgânico. (AU)

Wilson disease is an authossomal recessive disorder of copper metabolism that leads to the impregnation of the metal in different tissues such as the liver, brain, cornea and kidneys. There is a prevalence of 1:40,000 and evolution is progressive and fatal if untreated. The diagnosis depends on clinical suspicion and laboratory tests, and may be difficult in situations such as the asymptomatic patients or with severe liver insufficiency. The classic triad presentation is the hepatic, neurological and ophthalmologic disease. In children, the most common is the hepatic (acute or chronic). The diagnosis criteria are based on the presence of low ceruloplasmine, elevated copper in 24-hour urine and high seric copper and ophthalmologic evaluation in search of Kayser Fleischer ring. The medication treatment must be established as soon as possible so as to prevent tissue lesions due to copper excess, hence the great importance of early diagnosis. The drug choice is the D-penicilamin, with careful monitoring of side effects and attention for occasional worsening of the neuropsychiatric state. There are other drugs as trientine, tetratiomolibdato and zinc that also have an effect on the reduction of organic copper. (AU)

Effect of G protein in the dual regulation of opioid receptor agonist on the delayed rectified potassium channels / 中国医学科学院学报

<p><b>OBJECTIVE</b>To observe the role of G protein in the dual regulation of opioid receptor agonist on the delayed rectified potassium channels.</p><p><b>METHODS</b>Using whole-cell patch-clamp techniques applied to NG108-15 cells, investigate the effect of opioid receptor agonist on the delayed rectified potassium channels by administration of Guanosine-5'-0'-2-thiociphosphate (GDP beta S), Pertusis Toxin (PTX), Tetroacetic acid nueleoside diphosphate kinase (NDPK) and Adenosine-3' 5' cyclic monophosphate cAMP in the pipette solution.</p><p><b>RESULTS</b>(1) GDP beta S could block the changes induced by both high and low concentration of (D-Pen2.5)-enkephalin (DPDPE) (P < 0.05). (2) PTX could inhibit the excitative regulation on K+ channel by high concentration of DPDPE (P < 0.05). But CTX had no effect on K+ channel caused by DPDPE. (3) UDP could block the excitative effect of K+ channel by high concentration of NDPK, while have no changes on the inhibitory effect caused by low concentration of opioid agonists. (4) cAMP took part in the regulation in high concentration of agonist administration (P < 0.05), while no changes for low concentration of agonists.</p><p><b>CONCLUSIONS</b>Dual changes were observed on delayed rectifier potassium channel by agonist treatment on NG108-15 cells. The excitative effect was Gi/o coupled in high concentration of agonist incubation, related to cAMP. While the inhibitory effect was possibly induced by G protein beta gamma subunit directly.</p>

Dual regulation by delta opioid receptor agonists on the delayed rectified potassium channels in NG108-15 cells / 中国医学科学院学报

<p><b>OBJECTIVE</b>To investigate the dual effects by the delta opioid receptor agonists DPDPE on the delayed rectified potassium channels in NG108-15 cells.</p><p><b>METHODS</b>A series of outward currents were evoked in NG108-15 cells by depolarizing voltage from -50 mV to +80 mV at holding potential of -90 mV. These currents were delayed rectified potassium currents. Relatively selected delta opioid receptor agonists DPDPE of higher and lower concentrations were used to modulate the delayed rectified K+ current in NG108-15 cells. Opioid receptor antagonist Naloxone (NAL) and relatively selected delta opioid receptor antagonist Naltrindole (NTI) were used in the present experiments for the characterization of the actions of opioid receptors.</p><p><b>RESULTS</b>The relatively higher concentrations of delta opioid receptor agonist DPDPE (> or = 10(-6) mol/L) significantly increased the amplitude of the delayed rectified K+ current. On the contrary, the relatively lower concentrations of DPDPE (< or = 10(-12) mol/L) decreased the amplitude of the delayed rectified K+ current (P < 0.05). Furthermore both the increase and decrease were time-dependent.</p><p><b>CONCLUSIONS</b>delta opioid receptor agonist has dual regulatory effects on the delayed rectified potassium channels in NG108-15 cells.</p>

Regulation of 3HNorepinephrine Release by Opioids in Human Cerebral Cortex

To investigate the receptors mediating the regulation of norepinephrine (NE) release in human cerebral cortex slices, we examined the effects of opioid agonists for mu-, delta-, and kappa -receptors on the high potassium (15 mM) -evoked release of [3H]NE. [3H]NE release induced by high potassium was calcium-dependent and tetrodotoxin-sensitive. [D-Pen2, D-Pen5]enkephalin (DPDPE) and deltorphin II (Delt II) inhibited the stimulated release of norepinephrine in a dose-dependent manner. However, Tyr-D-Ala-Gly- (Me) Phe-Gly-ol and U69, 593 did not influence the NE release. Inhibitory effect of DPDPE and Delt-II was antagonized by naloxone, naltrindole, 7-benzylidenaltrexone and naltriben. These results suggest that both delta 1 and delta 2 receptors are involved in regulation of NE release in human cerebral cortex.

The postburn change in hypothalamic paraventricular beta-endorphin and the roles of delta-receptor in scalded rats / 中华烧伤杂志

<p><b>OBJECTIVE</b>To investigate the postburn change in hypothalamic paraventricular beta-endorphin and the roles of delta-receptor in scalded rats.</p><p><b>METHODS</b>Male Sprague-Dawley (SD) rats were randomly divided into 3 groups, i.e. ICI174864, DPDPE and control groups. The rats were inflicted with 20% TBSA of III degree scalding on the back by boiling (100 degrees ) water. The postburn change in the tissue content of the hypothalamic paraventricular beta-endorphin was determined by radioimmuno assay (RIA). The effects of delta-receptor in scalded shock rats were investigated by observing the change of the rats'survival time and cardiac indices after the micro-injection of delta-receptor agonist DPDPE or antagonist ICI174864 into the hypothalamic paraventricle.</p><p><b>RESULTS</b>(1) The tissue content of the hypothalamic paraventricular beta-endorphin increased significantly (P < 0.01) at 1, 2 and 4 postburn hours (PBHs) in the scalded rats. (2) When compared with that of control group, the ratio of the cardiovascular parameters [mean arterial pressure (MAP), dp/dt(max) and HR] were obviously increased at different time points in rats with pre-injection of ICI174864 whereas the ratio was decreased when DPDPE was used. Nevertheless, the change in the heart rate ratio was not obvious whether ICI174864 or DPDPE was used. (3) The average animal survival time in ICI174864 group was much longer than that in DPDPE group.</p><p><b>CONCLUSION</b>An excessive increase in hypothalamic paraventricular beta-endorphin was one of the factors leading to the aggravation of burn shock and earlier death. delta-receptor located in the tissue might have played important roles in the mediation of the action of hypothalamic paraventricular beta-endorphin. It is beneficial to antagonize the action of delta-receptor for the correction of burn shock and for the prolongation of the of life of animals.</p>